The Molecular Imaging Branch (MIB) aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as depression, addiction, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radioactive probes (radiotracers) that can be used with PET to deliver new and specific information on molecular entities and processes in the living animal or human brain (e.g., regional neuroreceptor concentrations, neurotransmitter synthesis, enzyme concentrations, regional metabolism, amyloid deposition, drug efflux from brain). PET is uniquely powerful and sensitive for this purpose, provided that it can be coupled to the use of appropriate PET radiotracers. The chemical development of these probes is the key to exploiting the full potential of PET in neuropsychiatric research, but is also widely recognized as being a highly challenging and demanding scientific task. Potential imaging targets far exceed the range of probes available. Our laboratory, the PET Radiopharmaceutical Sciences Section of the MIB, places a concerted effort on PET radiotracer discovery. This process has some parallels with drug discovery in terms of required effort and risk, because successful probes must fulfill a difficult-to-satisfy range of chemical, pharmacological and biological criteria. Our laboratories are equipped with modern facilities for performing medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). The two short-lived radioisotopes needed to support this research program are produced on a daily basis from the adjacent cyclotrons of the NIH Clinical Center. Our scientific program currently focuses on developing novel probes for imaging and quantifying several different brain receptors or proteins implicated in neuropsychiatric disorders e.g., cannabinoid (CB-1),serotonin (5-HT1A, 5-HT4), TSPO (formerly known as PBR), and glutamate (mGluR1,mGluR5)receptors, efflux transporters (P-gp) and protein deposits such as beta-amyloid. Research in some of these areas has already been successful, providing new radiotracers for CB-1, TSPO, mGluR5 and P-gp for brain imaging in human subjects in support of clinical research. This human research is conducted in collaborartion with the Imaging Section of the same Branch (Chief Dr. R.B. Innis) under Food and Drug Administration (FDA) oversight through 'exploratory'or full investigational new drug applications (expINDs or INDs). This Section also interacts seamlessly with the Imaging Section to evalaute potential radiotracers. Many candidate radiotracers were designed, prepared and evaluated in reaching our goals. Two radiotracers developed for TSPO imaging ((C-11)PBR28 and (F-18)FBR) appeared highly successful and are starting to have application for the investigation of brain inflammatory conditions in response to neurological insults e.g., traumatic brain injury, stroke, epilepsy and neurodegeneration (Alzhemier'sdisease). Other institutions (e.g., Cambridge University, Pitsburgh University)are also begining to use these radiotracers to perform clinical studies. An interesting and unexpected finding is that healthy human subjects may have different forms of TSPO that interact differently with (C-11)PBR28. Possible reasons for this finding, and its implications for TSPO imaging in patients, are being investigated with collaborators. New less discriminatory TSPO radioligands may be required. CB-1 receptors are the sites in the brain that are acted upon by cannabis. Our new CB-1 radiotracers ((C-11)MePPEP, (F-18)FMPEP) have potential for the study of drug addiction, including alcoholism and cocaine addiction. These probes may also have relevance to the study of other disorders, such as obesity. (C-11)MEPPEP has also entered use elsewhere. Our mGluR radiotracer ((F-18)SP203) is expected to have value for the study of Fragile X syndrome, addiction, autism and schizophrenia. Such PET radiotracers have additional value in expediting drug discovery (see for example the popular feature article entitled 'A Chemical Map of The Mind - Targeted radiotracers help drug makers navigate the neurological landscape by PET', published in Chemistry and Engineering News, Sep 8th, 2008, which discusses our mGluR radiotracer and other probes). The imaging of drug efflux pump (e.g., P-gp)function at the blood-brain barrier is a recent area of interest in our laboratory with relevance to drug development for neuropsychiatric disorders. We have developed a much improved radiotracer, named (C-11)dLop, for this purpose, which has now reached the level of study in human subjects. (C-11)dLop has clinical research potential for assessing the role of efflux pumps in Alzheimer's disease and other neurodegenerative disorders (e.g., Parkinson's disease). A radiotracer for imaging P-gp density is sought in addition to our radiotracer of function. Some of the radiotracers that we have developed are likely to have value for diseases that present outside the brain. Thus, the TSPO radiotracers may be generic for the study of inflammation in the periphery (e.g., as occurs in atherosclerosis), and the P-gp radiotracer for the study of cancer (especially multi-drug resistance). Methodology underpinning our radiotracer development was also advanced in areas such as the development of new synthetic methods, new radiolabeling procedures, and the application of micro-reactors to the miniaturization of radiochemistry. Over the past year, we have combined the use of microfluidics with a new F-18 labeling strategy to great effect, thereby expanding the number and type of candidate F-18 labeled radiotracers that may be produced. Such advances are seen as being vital for facilitating radiotracer applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry (LC-MS), have also been developed and exploited to understand the biochemical fate of radiotracers in living systems. This information is needed to fully understand the results from PET experiments and to derive meaningful output measures, such as brain receptor concentrations. Sensitive LC-MS has been introduced for the measurement of radiotracer half-life and specific radioactivity, and also for the measurement of radiotracer concentration in blood following intravenous administration. The use of LC-MS avoids the need to measure fast-decaying radioactivity. Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through CRADAs (Cooperative Research and Development Agreements) and the Biomarker Consortium of the Foundation for NIH. Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. The laboratory is active in training new scientists for this field at all levels. In addition, we produce several established radiotracers for PET investigations in animal or human subjects e.g.,(C-11)MNPA (functional D2 receptor imaging), (C-11)CUMI (5-HT1A receptor imaging), (C-11)AZ (5-HT1B receptor imaging), (C-11)rolipram (PDE4 enzyme imaging), and (C-11)PK 11195 (TSPO binding site imaging). The production of such radiotacers for use in in human subjects complies with (Food and Drug Administration) FDA requirements under exploratory or full Investigational New Drug applications (INDs). Each PET experiment with one of these radiotracers requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity. Approximately 400 productions are performed per annum.